Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning (n = 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p = 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes.

Key words::

• Amyotrophic lateral sclerosis
• respiratory insufficiency
• diaphragm
• diaphragm pacing
• sleep-related disturbances

Acknowledgements

This work was supported by grants from two patients’ associations – the Association pour la Recherche sur la Sclérose Latérale Amyotrophique (ARSla), Paris, and the Association Française contre les Myopathies (AFM), Paris. It was partially funded by Synapse Biomedical Inc., Oberlin, Ohio, USA, which provided the stimulators used at the French centre free of charge, took legal responsibility for the study according to French law on human research (liability insurance), and paid Technomics Research for statistical analysis.

Medical writing and editorial assistance were provided by Winnie McFadzean and Rosie Mallett. The corresponding funding was drawn from the grant provided by the Association pour la Recherche sur la Sclérose Latérale Amyotrophique (ARSla).

The authors are grateful to Lucette Lacomblez for her help at the initial stage of the project.

Funding was provided by Synapse Biomedical Inc., Association pour la Recherche sur la Sclérose Latérale Amyotrophique (ARSla), and Association Française contre les Myopathies (AFM).

Declaration of interest: Jesus Gonzalez-Bermejo received honoraria from Synapse Biomedical Europe for educational talks on intradiaphragmatic phrenic stimulation at two Spanish centres in 2008. Moustapha Diop is an employee and officer of Synapse Biomedical Inc., and owns equity in the company. Anthony Ignagni is an employee and officer of Synapse Biomedical Inc., owns equity in the company, and has intellectual property rights in the diaphragm pacing system. Raymond Onders owns equity in Synapse Biomedical Inc. and has intellectual property rights in the diaphragm pacing system. Case Western Reserve University and University Hospitals Case Medical Center also have equity and intellectual property rights in diaphragm pacing. Teresa Nelson is a part-owner of Technomics Research LLC, to which Synapse Biomedical Inc. paid per-hour fees for performing the statistical analysis. Fabrice Menegaux has been asked by Synapse Biomedical Inc. to train other European surgeons in the implantation procedure, in exchange for which Synapse paid a subsidy to the non-profit research association to which Fabrice Menegaux belongs (4000 euros paid in 2010). Thomas Similowski received honoraria for the translation from English to French of the technical and users’ manual of two respiratory neurostimulators (the ‘Atrostim’ in 2002 (Atrotech, Tampere, Finland) and the ‘NeurRxDP4’ in 2007 (Synapse Biomed., Oberlin, Ohio, USA)).

Thomas Similowski, Jesus Gonzalez-Bermejo, Capucine Morélot-Panzini, Christian Straus, Marie-Helene Becquemin and Isabelle Arnulf belong to a non-profit research association (ADOREP, Association pour le Développement et l'Organisation de la Recherche en Pneumologie) that received an unrestricted grant from Synapse Biomedical Europe, to support research on respiratory neurostimulation (3000 euros paid in 2010).

Capucine Morélot-Panzini, François Salachas, Isabelle Arnulf, Christian Straus, Marie-Hélène Becquemin, Pierre-François Pradat, and Vincent Meininger have no personal conflict of interest relevant to this study.